Increasing the optical purity of l-lysine monohydrochloride

ABSTRACT

A process for the purification of optically active lysine monohydrochloride, containing racemic lysine monohydrochloride as an optical impurity, is disclosed. In this process the solid salt is treated with water to effect an at least partial dissolution or extraction of the optical antipod of the lysine monohydrochloride which is present in the original salt. The aqueous solution thus formed is separated from the solid phase before an equilibrium state is reached, the solid phase thus obtained being of lower optical purity than the original salt.

United States Patent Albertus H. Pecasse;

Geleen, Netherlands [21] Appl. No. 695,360 [22] Filed Jan. 3, 1968 [45]Patented Sept. 21, 1971 [73] Assignee Stamicarbon N. V.

Heerlen, Netherlands [32] Priority Jan. 11, 1967 [3 3 Netherlands [3 16700368 [54] INCREASING THE OPTICAL PURITY OF L- LYSINEMONOHYDROCHLORIDE Primary Examiner-Charles B. Parker AssistantExaminer-Jacqueline L. Davison Attorney-Cushman, Darby & CushmanABSTRACT: A process for the purification of optically activelysinemonohydrochloride, containing racemic lysine monohydrochloride as anoptical impurity, is disclosed. In this process the solid salt istreated with water to effect an at least partial dissolution orextraction of the optical antipod of the lysine monohydrochloride whichis present in the original salt. The aqueous solution thus formed isseparated from the solid phase before an equilibrium state is reached,the solid phase thus obtained being of lower optical purity than theoriginal salt.

INCREASING THE'OPTICAL PURITY OF L-LYSINE MONOHYDROCHLORIDE Theinvention relates to a process for increasing the optical purity ofoptically active lysine monohydrochloride containing DL-lysinemonohydrochloride as an optical impurity. The process comprises removingtherefrom a fraction containing DL-lysine monohydrochloride and havingan optical purity lower than that of the original lysinemonohydrochloride. The remaining lysine monohydrochloride then has ahigher optical purity than the original lysine monohydrochloride.

According to the process described in US. Pat. Specification No.3,131,216, L-lysine monohydrochloride of high optical purity can beobtained by preparing an unsaturated aqueous solution of L-lysinemonohydrochloride containing DL- isomer, and having an optical purityof, say, 95 percent. The solution can then be concentrated byevaporation until the amount of water remaining corresponds only to theamount needed for forming a saturated solution of the available amountof pure L-lysine monohydrochloride at a predetermined lower saturationtemperature. The concentrated solution can then be cooled to saidsaturation temperature and, with a simultaneous addition of DL-lysinemonohydrochloride as a seed material, a solid substance will becrystallized and subsequently separated at said saturation temperature.

The crystallized lysine monohydrochloride which thus separates fromsolution has a lower, and the lysine monohydrochloride left in thesolution a higher, optical purity, than the original impure L-lysinemonohydrochloride. The L-lysine monohydrochloride of thusly increasedoptical purity can then be recovered from the solution in the solidstate, for example by spray drying.

The execution of this known process is based on the circumstance thatDL-lysine monohydrochloride is itself only slightly soluble in anaqueous solution saturated with L-lysine monohydrochloride (the sameholds, of course, in the case of an aqueous solution saturated withD-lysine monohydrochloride). It has now appeared, however, thatnotwithstanding the addition of seed material, the DL-lysinemonohydrochloride phase crystallizes only very irregularly from theconcentrated solution at the saturation temperature. Occasionally therequired crystallization takes place only after an unreasonably longtime. Due to this irregular crystallization at an accurately definedtemperature, industrial realization of this known process has been anextremely costly proposition.

It is an object of the present invention to provide an improved processfor increasing the optical purity of optically active, but impure,lysine monohydrochloride, which can be realized on a large scale in asimple manner.

This new process is characterized by'the steps of treating solid lysinemonohydrochloride which is optically active, but still containing aportion of DL-lysine monohydrochloride, and while still in the solidstate, with an amount of water to effect partial dissolution of thesolid material present, and separating the solid phase from the liquidphase before sufficient time has passed to establish an equilibriumstate.

Surprisingly, it has been found that in this way a solid phase,containing DL-lysine monohydrochloride, can be isolated having anoptical purity lower than that of the original lysine monohydrochloride,so that the lysine monohydrochloride in the resulting aqueous solutionhas an optical purity higher than that of the original lysinemonohydrochloride. In effect, the optical antipod present in theoriginal solid salt is preferentially dissolved or extracted into theaqueous medium. Preferably at least 70 percent of the quantity ofoptical antiopod present in the original solid salt beside the DL-lysinemonohydrochloride, is dissolved or extracted into the aqueous medium.

if desired, the dissolved lysine monohydrochloride of enhanced opticalpurity can then be recovered from the aqueous solution in the solidstate and in the same manner as with the known procedure. The isolatedsolid phase of decreased optical purity can then be subjected to opticalresolution by other known procedures.

This process according to the invention can be carried out at severaltemperatures. Other conditions being kept equal, at higher temperatures,more lysine monohydrochloride will go into solution, but the opticalpurity of the dissolved lysine monohydrochloride will then be lower. Atlower temperatures, but under otherwise identical conditions, on theother hand, less lysine monohydrochloride will go into solution, but theoptical purity of the lysine monohydrochloride in the resulting solutionwill then be higher. To balance these two considerations, preferably,temperatures in the range of about 40-80 C. are employed.

The solid lysine monohydrochloride used in the process according to theinvention may or may not contain water of crystallization. The use ofsolid lysine monohydrochloride containing water of crystallization has.the advantage that the period of time of the mixing operation can betaken shorter.

The water used in the process according to the invention need not bepure water. If, for example, the water already contains some dissolvedlysine monohydrochloride, the desired goal can also be achieved. In theevent the original solid lysine monohydrochloride is contaminated withother substances, generally there is no hindrance in neverthelesspracticing the process. i

In the process according to the invention, the ratio between the amountof water and the amount of solid lysine monohydrochloride may be varied.

Use of larger amounts of water, under otherwise identical conditionswill cause more lysine monohydrochloride to go into solution, but thiswill have a lower optical purity whereas the use of a smaller amount ofwater will produce the opposite effect.

Use of an amount of water such that no solid substance would be presentanymore in the equilibrium state, may also produce the result envisagedby the invention, because according to the invention the mixingoperation is terminated before an equilibrium state is reached and thenthere is always a solid phase present. Optimum results can be obtainedif the total amount of water (inclusive of water of crystallization, ifany) in the mixture corresponds to the amount of water, which at thetemperature at which the mixing of the solid lysine monohydrochloridewith the water is terminated, would be required to form a saturated, orsubstantially saturated, solution of the quantity of pure opticalantipod present in the original solid lysine monohydrochloride. Such anamount of water is also used in the known process. Surprisingly, it hasbeen found that if this amount of water is used in the process accordingto the present invention, the lysine monohydrochloride in the resultingaqueous solution has a higher optical purity than it would have atequilibrium under otherwise identical conditions, This affords animportant advantage over the known process wherein in the maximumoptical purity which can be achieved for the dissolved lysinemonohydrochloride in the solution can never be higher than the valuecorresponding to the state of equilibrium.

If other amounts of water are used, other points of equilibrium may beestablished between a solid phase containing DL- isomer and having anoptical purity lower than that of the original lysine monohydrochlorideand a liquid phase containing dissolved lysine monohydrochloride of anoptical purity higher than that of the original lysinemonohydrochloride. lf, however, in such an event, the nondissolved solidphase is separated off, according to the invention before an equilibriumstate has established, the optical purity of the lysinemonohydrochloride in the solution appears to be higher than the valuecorresponding to the state of equilibrium.

In addition to the parameters mentioned above, the period of time inwhich the solid lysine monohydrochloride is mixed with the water, may bevaried in the process according to the invention. This period should, ofcourse, be shorter than that required for establishment of theequilibrium. This is not a problem, however, because, extreme conditionsbeing left aside, the equilibrium is established only very slowly.Excellent results can be obtained by mixing for 20-40 minutes.

The examples given hereinafter are meant to elucidate the inventionwithout limiting its scope in any way whatsoever.

EXAMPLE 1 Two-hundred thirty-six and four-tenths g. of L-lysinemonohydrochloride containing DL-isomer and having an optical purity of92.4 percent (100 g. of anhydrous lysine monohydrochloride consists of84.8 g. L-isomer and 15.2 g. DL-isomer) and a water of crystallizationcontent equal to 15.4 percent by wt. are well stirred with 87.5 g. ofwater at 60 C. for approximately 30 minutes. The resulting mixture thuscontains a total amount of water equal to 123.9 g., together with 169.6g. of pure L-lysine monohydrochloride corresponding to a saturationconcentration of pure L-lysine monohydrochloride in water at 60 C.

The undissolved solid substance is removed by filtration. This leaves281.3 g. of aqueous solution containing 56.6 percent by wt. of L-lysinemonohydrochloride of 99.1 percent optical purity. (If stirring at 60 C.is continued until equilibrium has established, the optical purity ofthe L-lysine monohydrochloride in the aqueous solution is only 98percent). Spray drying of the remaining aqueous solution yields 160 g.of solid L-lysine monohydrochloride with a water content of 0.5 percentby wt. and an optical purity of, likewise, 99.1 percent.

EXAMPLE 2 Two-hundred thirty-four and two-tenths g. of L-lysinemonohydrochloride containing DL-isomer and having an optical purity of92.4 percent and a water of crystallization content equal to 14.7percent by wt. are well stirred with 110.3 g. of water at 65 C. forapproximately 30 minutes, after which the nondissolved solid substanceis removed by filtration. This leaves 309.4 g. of an aqueous solutioncontaining 53.6 percent by wt. of L-lysine monohydrochloride of 98.2percent optical purity. (If stirring at 65 C. is continued untilequilibrium has established, the optical purity is only 97 percent).

The aqueous solution is cooled down to 15 C., and thereafter thecrystallized product is removed by centrifuging. This yields 105 g. of acrystalline mass containing 82.1 percent by wt. of L-lysinemonohydrochloride of 99.1 percent optical purity.

The remaining mother liquid contains 79.6 percent of L- lysinemonohydrochloride of 97 percent optical purity. The L- lysinemonohydrochloride can be recovered in the solid state from this motherliquor in the known manner, after which the optical purity can beincreased in the way described above.

EXAMPLE 3 Two-hundred thirty-five and seven-tenths g. of L-lysinemonohydrochloride containing DL-isomer and having an optical purity of95.2 percent and a water of crystallization content equal to 15.1percent by wt. are well mixed with 84.3 g. of water at 55 C for 30minutes, after which the nondissolved solid substance is removed byfiltration. This leaves 243.2 g. of an aqueous solution containing 54.6percent by wt. of L-lysine monohydrochloride of 99.2 percent opticalpurity. Spray-drying this solution yields 133.5 g. of solid L-lysinemonohydrochloride of the same optical purity, and with a water contentof 0.6 percent by wt.

EXAMPLE 4 Two-hundred-thirty and eight-tenths g. of L-lysinemonohydrochloride containing DL-isomer and having an optical purity of90.4 percent and a water of crystallization content equal to 13.3percent by wt. are well stirred with 87.2 g. of water at 55 C. for 30minutes. Next, the nondissolved solid substance is removed byfiltration. This leaves 246.6 g. of

aqueous solution containing 54.7 percent by wt. of L-lysinemonohydrochloride of 98.5 percent optical purity. Subsequently, theaqueous solution is cooled down to 20 C. and thereafter the crystallizedsolid product 18 removed by centrifuging. This yields 84.8 g. of solidmaterial containing 83.4 percent by wt. of L-lysine monohydrochloride of99.4 percent optical purity.

EXAMPLE 5 nondissolved solid substance is removed by filtration. Thisleaves 142.3 g. of an aqueous solution containing 57.3 percent by wt. ofL-lysine monohydrochloride of 98.5 percent optical purity.

EXAMPLE 6 One-hundred g. of solid L-lysine monohydrochloride containingDL-isomer and having an optical purity of 92.4 percent and a watercontent of 1.0 percent by wt. are well mixed with 61.2 g. of water at 60C. for 35 minutes, after which the nondissolved solid substance isremoved by filtration. This leaves 134.7 g. of an aqueous solutioncontaining 56.0 percent by wt. of L-lysine monohydrochloride of 98.9percent optical purity.

Those skilled in the art will appreciate that this invention may bepracticed by techniques other than those specifically illustrated in theexamples and in accordance with the spirit and scope of the followingclaims.

What is claimed is: l. A process which consists essentially in addingwater to lysine monohydrochloride in a particulate solid state,

which lysine monohydrochloride is optically active L-lysinemonohydrochloride together with a portion of racemic lysinemonohydrochloride, mixing said lysine monohydrochloride and water toeffect partial dissolution of the solid material into the aqueous phase,and then separating the undissolved solid phase from the liquid aqueousphase before an equilibrium state is reached,

whereby a solid phase of lysine monohydrochloride is obtained having alower optical purity than the original solid lysine monohydrochloride,and a liquid aqueous phase containing optically active L-lysinemonohydrochloride of increased optical purity with respect to theoriginal solid lysine monohydrochloride.

2. The process of claim 1, wherein said mixing of said solid lysinemonohydrochloride and water is effected at a temperature between about40 and C.

3. The process according to claim 1, wherein said solid lysinemonohydrochloride contains water of crystallization.

4. The process of claim 1, wherein the total amount of water employed,

including the water of crystallization present, corresponds to theamount of water, which, at the temperature at which the mixing of thesolid lysine monohydrochloride with the water is terminated, would beneeded to form an at least substantially saturated solution of thequantity of pure optical antipod present in said solid lysinemonohydrochloride.

5. The process according to claim 1, wherein said original solid lysinemonohydrochloride has an optical purity of at least about 80 percent.

6. The process according to claim 1, wherein at least 70 percent of thequantity of optical antipod present in the original solid salt besidethe DL-lysine monohydrochloride, is dissolved into the aqueous phase.

2. The process of claim 1, wherein said mixing of said solid lysinemonohydrochloride and water is effected at a temperature between about40 and 80* C.
 3. The process according to claim 1, wherein said solidlysine monohydrochloride contains water of crystallization.
 4. Theprocess of claim 1, wherein the total amount of water employed,including the water of crystallization present, corresponds to theamount of water, which, at the temperature at which the mixing of thesolid lysine monohydrochloride with the water is terminated, would beneeded to form an at least substantially saturated solution of thequantity of pure optical antipod present in said solid lysinemonohydrochloride.
 5. The process according to claim 1, wherein saidoriginal solid lysine monohydrochloride has an optical purity of atleast about 80 percent.
 6. The process according to claim 1, wherein atleast 70 percent of the quantity of optical antipod present in theoriginal solid salt beside the DL-lysine monohydrochloride, is dissolvedinto the aqueous phase.